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    Clinical Trial Results:
    A Two Year, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of Teriflunomide Administered Orally Once Daily in Pediatric Patients With Relapsing Forms of Multiple Sclerosis Followed by an Open-label Extension

    Summary
    EudraCT number
    		 2011-005249-12
    Trial protocol
    		 EE   BE   ES   GR   PL   GB   FR   LT   Outside EU/EEA   IE   NL   BG   PT   SI   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    29 Jan 2021
    First version publication date
    29 Jan 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC11759
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02201108
    WHO universal trial number (UTN)
    		 U1111-1124-0983
    Sponsors
    Sponsor organisation name
    Genzyme, a Sanofi Company
    Sponsor organisation address
    50 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001094-PIP01-10
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    27 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of teriflunomide in comparison to placebo on disease activity as measured by time to first clinical relapse after randomisation in children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia might have been used to minimise distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Turkey: 32
    Country: Number of subjects enrolled
    China: 37
    Country: Number of subjects enrolled
    Morocco: 2
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Lebanon: 4
    Country: Number of subjects enrolled
    Tunisia: 4
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Ukraine: 7
    Worldwide total number of subjects
    166
    EEA total number of subjects
    35
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    16
    Adolescents (12-17 years)
    150
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 57 active centres in 21 countries. A total of 185 subjects were screened between 16 July 2014 and 27 December 2017, of which 166 subjects were enrolled and randomised. A total of 19 subjects failed screening mainly due to meeting exclusion criteria.

    Pre-assignment
    Screening details
    		 Subjects were randomly assigned to receive either teriflunomide or placebo in a 2:1 ratio (109 teriflunomide and 57 placebo) via Interactive Voice Response System. Randomisation was stratified by the country and subject's pubertal status. Data reported based on the primary completion date of 25 October 2019.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matching to teriflunomide tablet orally once daily (QD) for 96 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single tablet of placebo (matched to teriflunomide) was administered orally QD with or without food in the morning preferably at the same time each day of the double-blind treatment period (i.e., 96 weeks).

    Arm title
    		 Teriflunomide
    Arm description
    		 Subjects received 1 Teriflunomide tablet, 3.5 milligrams (mg) (in case of body weight [BW] up to 40 kilograms [kg]) or 7 mg (in case of BW greater than [>]40 kg) orally QD for 8 weeks. After 8 weeks, based on subjects predicted pharmacokinetic (PK) parameters, teriflunomide was administered in following manner up to 96 weeks:if predicted PK parameters less than or equal to (<=)95th percentile of adult range after 7 mg QD:1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW>40 kg);or if predicted PK parameters >95th percentile of adult range:1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW>40 kg). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as maximum concentration observed (Cmax) ranging from 8.03 to 49.10 micrograms per millilitre (mcg/mL) and area under the curve from time 0 hour to 24 hours (AUC0-24) ranging from 184 to 1160 micrograms*hour per millilitre (mcg*h/mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriflunomide
    Investigational medicinal product code
    AUBAGIO, HMR1726
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Teriflunomide (3.5 mg or 7 mg or 14 mg) film-coated tablet was administered orally QD with or without food in the morning preferably at the same time each day of the double-blind treatment period (i.e., 96 weeks).

    Number of subjects in period 1
    		Placebo Teriflunomide
    Started
    57
    109
    On-going subjects
    0 [1]
    58 [2]
    Completed
    53
    102
    Not completed
    4
    7
         Consent withdrawn by subject
    2
    -
         Adverse Event
    -
    6
         Lack of efficacy
    2
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: On-going subjects represent the 58 subjects of Teriflunomide arm who entered the open-label period post double-blind treatment period.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: On-going subjects represent the 58 subjects of Teriflunomide arm who entered the open-label period post double-blind treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matching to teriflunomide tablet orally once daily (QD) for 96 weeks.

    Reporting group title
    Teriflunomide
    Reporting group description
    		 Subjects received 1 Teriflunomide tablet, 3.5 milligrams (mg) (in case of body weight [BW] up to 40 kilograms [kg]) or 7 mg (in case of BW greater than [>]40 kg) orally QD for 8 weeks. After 8 weeks, based on subjects predicted pharmacokinetic (PK) parameters, teriflunomide was administered in following manner up to 96 weeks:if predicted PK parameters less than or equal to (<=)95th percentile of adult range after 7 mg QD:1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW>40 kg);or if predicted PK parameters >95th percentile of adult range:1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW>40 kg). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as maximum concentration observed (Cmax) ranging from 8.03 to 49.10 micrograms per millilitre (mcg/mL) and area under the curve from time 0 hour to 24 hours (AUC0-24) ranging from 184 to 1160 micrograms*hour per millilitre (mcg*h/mL).

    Reporting group values
    		 Placebo Teriflunomide Total
    Number of subjects
    		 57 109 166
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.7 ± 2.1 14.6 ± 2.0 -
    Gender categorical
    Units: Subjects
        Female
    		 39 72 111
        Male
    		 18 37 55
    Race
    Units: Subjects
        Caucasian/White
    		 42 75 117
        Black
    		 1 4 5
        Asian/Oriental
    		 12 25 37
        Other
    		 2 5 7

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matching to teriflunomide tablet orally once daily (QD) for 96 weeks.

    Reporting group title
    Teriflunomide
    Reporting group description
    		 Subjects received 1 Teriflunomide tablet, 3.5 milligrams (mg) (in case of body weight [BW] up to 40 kilograms [kg]) or 7 mg (in case of BW greater than [>]40 kg) orally QD for 8 weeks. After 8 weeks, based on subjects predicted pharmacokinetic (PK) parameters, teriflunomide was administered in following manner up to 96 weeks:if predicted PK parameters less than or equal to (<=)95th percentile of adult range after 7 mg QD:1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW>40 kg);or if predicted PK parameters >95th percentile of adult range:1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW>40 kg). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as maximum concentration observed (Cmax) ranging from 8.03 to 49.10 micrograms per millilitre (mcg/mL) and area under the curve from time 0 hour to 24 hours (AUC0-24) ranging from 184 to 1160 micrograms*hour per millilitre (mcg*h/mL).

    Subject analysis set title
    Teriflunomide 7 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects with BW >40 kg received 1 Teriflunomide tablet, 7 mg orally QD for 8 weeks. After 8 weeks, based on subject's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg).

    Subject analysis set title
    Teriflunomide 14 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    After 8 weeks, based on subject's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg).

    Primary: Time to First Confirmed Clinical Relapse

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    End point title
    		 Time to First Confirmed Clinical Relapse
    End point description
    Time to first clinical relapse:duration (in weeks) between randomisation & first confirmed clinical relapse. Clinical relapses:new/recurrent neurological symptoms not associated with fever/infection, lasted at least 24 hours & accompanied by new objective neurological findings upon neurological examination & documented by standardised, quantified functional system score (FSSs) which included 8 items:rated on different scales:brain stem, cerebellar & cerebral functions rated on scale of 0 to 5;visual, pyramidal, sensory & bowel/bladder rated on scale of 0 to 6 & ambulation on scale of 0 to 12 where higher score in each scale indicated worsened neurological function. Confirmed clinical relapse were reviewed & confirmed by independent Relapse Adjudication Panel. Subject without confirmed clinical relapse;considered as clinical relapse free until end of Week 96. Analysed on Intent-to-treat (ITT) population:all randomised subjects analysed according to treatment allocated by randomisation.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: weeks
        median (full range (min-max))
    39.14 (0.1 to 98.0)
    75.29 (0.1 to 98.7)
    Statistical analysis title
    		 Teriflunomide versus Placebo
    Statistical analysis description
    Hazard ratio (HR) was estimated using a Cox proportional-hazards model with factors for treatment group, region, pubertal status, age, and number of relapses in the year prior to randomisation as covariates and with robust variance estimation. Derived from log-rank test with stratification of region and pubertal status.
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2949 [1]
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.657
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.388
         upper limit
    		 1.113
    Notes
    [1] - Threshold for significance was < 0.05.

    Secondary: Probability of Subjects Who Were Clinical Relapse Free at Weeks 24, 48, 72 and 96

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    End point title
    		 Probability of Subjects Who Were Clinical Relapse Free at Weeks 24, 48, 72 and 96
    End point description
    Subject was considered free of clinical relapse if the subject had no confirmed clinical relapse before treatment discontinuation/completion in 96 weeks treatment period. Clinical relapses: new/recurrent neurological symptoms not associated with fever/infection, lasted at least 24 hours, & accompanied by new objective neurological findings upon neurological examination & documented by standardised, quantified FSSs which included 8 items: rated on different scales: brain stem, cerebellar & cerebral functions rated on scale of 0 to 5; visual, pyramidal, sensory & bowel/bladder rated on scale of 0 to 6 & ambulation on scale of 0 to 12, where higher score in each scale indicated worsened neurological function. New/recurrent symptoms occurred less than 30 days following onset of relapse were considered part of same relapse. Probability of subjects who were clinical relapse free at specified weeks was estimated by Kaplan-Meier method and reported. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 24, 48, 72 and 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: probability of relapse free subjects
    number (confidence interval 95%)
        Week 24
    0.750 (0.615 to 0.844)
    0.807 (0.720 to 0.870)
        Week 48
    0.590 (0.444 to 0.710)
    0.684 (0.587 to 0.763)
        Week 72
    0.531 (0.379 to 0.662)
    0.619 (0.517 to 0.705)
        Week 96
    0.455 (0.293 to 0.603)
    0.594 (0.491 to 0.683)
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan

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    End point title
    		 Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan
    End point description
    Number of new or enlarged T2 lesions per scan was defined as the total number of new or enlarged T2 lesion that occurred during the 96 weeks treatment period divided by the total number of scans performed during 96 weeks. To account for the different numbers of scans performed among the subjects, a negative binomial regression model with robust variance estimation was used. The model included the total number of new or enlarged T2-lesions as the response variable, with treatment group, region, pubertal status and age as covariates and log-transformed number of scans as an offset variable. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: lesions per scan
        number (confidence interval 95%)
    10.515 (4.705 to 23.500)
    4.735 (2.122 to 10.567)
    Statistical analysis title
    		 Teriflunomide versus Placebo
    Statistical analysis description
    A hierarchical testing method was used to control Type-I error. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 5%.
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006 [2]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Relative risk ratio
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.285
         upper limit
    		 0.711
    Notes
    [2] - Negative binomial regression model with robust variance estimation: total number of new/enlarged T2-lesions as response variable;treatment group, region, baseline pubertal status & age as covariates;log-transformed number of scans as offset variable.

    Secondary: Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan

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    End point title
    		 Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan
    End point description
    The number of T1 Gd-Enhancing lesions per scan was defined as the total number of lesions that occurred during the 96 weeks treatment period divided by the total number of scans performed during 96 weeks. To account for the different number of scans performed among the subjects, a negative binomial regression model with robust variance estimation was used. The model included the total number of T1-lesions as the response variable, with treatment group, region, pubertal status and age as covariates and log-transformed number of scans as an offset variable. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: lesions per scan
        number (confidence interval 95%)
    7.505 (2.482 to 22.695)
    1.897 (0.656 to 5.489)
    Statistical analysis title
    		 Teriflunomide versus Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (hypothesis formally tested only if the preceding endpoint was significant at 5%).
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Relative risk ratio
    Point estimate
    0.253
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.126
         upper limit
    		 0.505
    Notes
    [3] - P-value and relative risk ratio was calculated by negative binomial regression model with robust variance estimation: total number of T1 Gd-enhancing T1 lesions as response variable, treatment group, region, baseline T1 Gd-enhancing T1 lesion count, baseline pubertal status and age as covariates and log-transformed number of scans as offset variable.
    [4] - Negative binomial regression model with robust variance estimation: total number of T1 Gd-enhancing T1 lesions as response variable, treatment group, region, pubertal status & age as covariates and log-transformed number of scans as offset variable.

    Secondary: Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 48, 72 and 96

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    End point title
    		 Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 48, 72 and 96
    End point description
    Volume of T2 lesions was measured by MRI scan. Analysis was performed on ITT population. Here, ‘n’ = number of subjects analysed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48, 72 and 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: millilitres
    least squares mean (standard error)
        Week 24 (n = 44, 96)
    0.148 ± 0.047
    0.075 ± 0.042
        Week 48 (n = 24, 72)
    0.135 ± 0.051
    0.060 ± 0.044
        Week 72 (n = 18, 64)
    0.204 ± 0.054
    0.065 ± 0.045
        Week 96 (n = 16, 54)
    0.201 ± 0.054
    0.073 ± 0.045
    Statistical analysis title
    		 Week 24: Teriflunomide versus Placebo
    Statistical analysis description
    Analysis performed using a Mixed-effect model with repeated measures (MMRM) adjusted for pubertal status, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0462 [5]
    Method
    		 MMRM
    Parameter type
    		 Least Square (LS) Mean difference
    Point estimate
    -0.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.144
         upper limit
    		 -0.001
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.036
    Notes
    [5] - P-value and LS Mean difference was calculated by MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
    Statistical analysis title
    		 Week 48: Teriflunomide versus Placebo
    Statistical analysis description
    Analysis performed using a MMRM adjusted for pubertal status, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0917 [6]
    Method
    		 MMRM
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.074
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.161
         upper limit
    		 0.012
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.044
    Notes
    [6] - P-value and LS Mean difference was calculated by MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
    Statistical analysis title
    		 Week 72: Teriflunomide versus Placebo
    Statistical analysis description
    Analysis performed using a MMRM adjusted for pubertal status, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0052 [7]
    Method
    		 MMRM
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.139
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.235
         upper limit
    		 -0.043
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.048
    Notes
    [7] - P-value and LS Mean difference was calculated by MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
    Statistical analysis title
    		 Week 96: Teriflunomide versus Placebo
    Statistical analysis description
    Analysis performed using a MMRM adjusted for pubertal status, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [8]
    Method
    		 MMRM
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.225
         upper limit
    		 -0.031
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.049
    Notes
    [8] - P-value and LS Mean difference was calculated by MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.

    Secondary: Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions

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    End point title
    		 Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions
    End point description
    Volume of T1 hypointense lesions was measured by MRI scan. Analysis was performed on ITT population. Here, ‘n’ = number of subjects analysed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48, 72 and 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: millilitres
    arithmetic mean (standard deviation)
        Week 24 (n = 44, 96)
    0.4 ± 1.3
    0.0 ± 0.7
        Week 48 (n = 23, 72)
    0.2 ± 0.6
    0.3 ± 2.8
        Week 72 (n = 18, 63)
    0.1 ± 0.7
    0.1 ± 0.6
        Week 96 (n = 16, 53)
    0.1 ± 0.5
    0.1 ± 0.7
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan

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    End point title
    		 Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan
    End point description
    The number of new T1 hypointense lesions were obtained from MRI scans. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: lesions
        number (not applicable)
    714
    848
    Statistical analysis title
    		 Teriflunomide versus Placebo
    Statistical analysis description
    P-value and relative risk ratio was calculated by negative binomial regression model with robust variance estimation, with total number of new hypointense T1 lesions as response variable, with treatment group, region, baseline pubertal status and age as covariates and log-transformed number of scans as an offset variable.
    Comparison groups
    Placebo v Teriflunomide
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0236 [9]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Relative risk ratio
    Point estimate
    0.507
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.281
         upper limit
    		 0.913
    Notes
    [9] - Negative binomial regression model with robust variance estimation:total number of new T1 hypointense lesions as response variable;treatment group, region, baseline pubertal status & age covariates; log-transformed number of scans as offset variable.

    Secondary: Magnetic Resonance Imaging Assessment: Percentage of Subjects Free of New or Enlarged MRI T2-Lesions

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    End point title
    		 Magnetic Resonance Imaging Assessment: Percentage of Subjects Free of New or Enlarged MRI T2-Lesions
    End point description
    Percentage of subjects who were free of new or enlarged T2 lesions at Weeks 48 and 96 were reported. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Weeks 48 and 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: percentage of subjects
    number (not applicable)
        Week 48
    10.5
    17.4
        Week 96
    3.5
    10.1
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 48, 72 and 96

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    End point title
    		 Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 48, 72 and 96
    End point description
    Percent change from baseline in brain volume (assessed using MRI scans of the Brain) at Weeks 24, 48, 72 and 96 was reported. Analysis was performed on ITT population. Here, ‘n’ = number of subjects analysed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48, 72 and 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: percent change
    arithmetic mean (standard deviation)
        Week 24 (n =42, 90)
    -0.3 ± 0.7
    -0.2 ± 0.8
        Week 48 (n =23, 68)
    -0.5 ± 1.0
    -0.5 ± 0.9
        Week 72 (n =18, 58)
    -0.8 ± 1.2
    -0.7 ± 1.1
        Week 96 (n =15, 50)
    -0.9 ± 1.2
    -0.8 ± 1.1
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Total Number of Correct Substitutions Measured by Symbol Digit Modalities Test (SDMT) at Weeks 24, 48, 72 and 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Total Number of Correct Substitutions Measured by Symbol Digit Modalities Test (SDMT) at Weeks 24, 48, 72 and 96
    End point description
    SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The score is the number of correct substitution and ranged from 0 (worst outcome) to 110 (best outcome), where higher score indicated better cognitive function. Analysis was performed on ITT population. Here, ‘n’ = number of subjects analysed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48, 72 and 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 24 (n = 44, 94)
    4.6 ± 11.6
    4.8 ± 9.2
        Week 48 (n = 24, 69)
    6.2 ± 13.5
    6.1 ± 10.3
        Week 72 (n = 19, 63)
    7.0 ± 12.7
    6.0 ± 11.2
        Week 96 (n = 16, 53)
    9.1 ± 10.9
    8.3 ± 11.1
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Number of Completed Items Measured by Symbol Digit Modalities Test at Weeks 24, 48, 72 and 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Number of Completed Items Measured by Symbol Digit Modalities Test at Weeks 24, 48, 72 and 96
    End point description
    SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The score is the number of completed items and ranged from 0 (worst outcome) to 110 (best outcome), where higher score indicated better cognitive function. Analysis was performed on ITT population. Here, ‘n’ = number of subjects analysed for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48, 72 and 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    57
    109
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 24 (n = 44, 94)
    3.4 ± 11.3
    3.8 ± 9.0
        Week 48 (n = 24, 69)
    5.4 ± 13.3
    5.0 ± 10.1
        Week 72 (n = 19, 63)
    5.6 ± 13.0
    4.8 ± 11.0
        Week 96 (n = 16, 53)
    7.6 ± 11.0
    7.1 ± 11.1
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Week 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Week 96
    End point description
    The BVMT consists of three trials in which subjects must recall shapes by drawing figures on a blank page (response booklet) after being given the opportunity to memorise the figures (given in BMVT-R form) for 10 seconds. BMVT-R form consists of six figures. Points are awarded based on the accuracy of the drawn figure and by correct placement on the blank page. A minimum of 0 to 12 points/scores are awarded per trial, so a subject can score between 0 and 36 points for all three trials (by adding the points/score from each trial), where higher score indicates better outcome. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    7
    36
    Units: score on a scale
        arithmetic mean (standard deviation)
    1.9 ± 10.7
    0.8 ± 6.0
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96
    End point description
    'Trail Making Test Part A' is a neuropsychological test of visual attention and task switching. The task requires a subject to 'connect-the-dots' of 25 consecutive numbers (1, 2, 3,etc.) in sequential order on a sheet of paper or computer screen. The goal of the subject is to finish the test as quickly as possible, and the time taken to complete the test used as the primary performance metric (in seconds). This is a timed test and the number of seconds to complete the task is recorded. Maximum time allowed is 300 seconds. A lower score indicated better cognitive function. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    4
    13
    Units: seconds
        arithmetic mean (standard deviation)
    3.8 ± 11.8
    -3.1 ± 19.5
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Week 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Week 96
    End point description
    TMT-B is a cognitive test that gives a measure of various aspects of cognitive performance. It is used to measure cognitive fatigue. The test consists of 25 circles containing 13 sequential numbers (1-13) and 12 sequential letters (A-L) positioned. The test evaluates the time (in seconds) to correctly order letters and numbers in alternate order (1, A, 2, B etc.). Maximum time allowed is 300 seconds, where less time/lower score indicates better cognitive function/performance. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    4
    13
    Units: seconds
        arithmetic mean (standard deviation)
    -14.4 ± 29.6
    -29.5 ± 56.6
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Week 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Week 96
    End point description
    The Beery VMI is a non-verbal assessment that assessed the extent to which individuals can integrate their visual and motor abilities. The subjects were provided with geometric designs ranging from simple line drawings to more complex figures and were asked to copy the designs. The test consisted of 24 figures. One point was scored for each successful copy of drawings and no scoring was given when the subject failed to copy the drawings properly. Each successful copying of drawings was summed up and the total was scored on a scale ranged from 0 to 24, where higher score indicated better visual construction skills/better visual and motor abilities and lower score indicated poor visual construction skills/poor visual and motor abilities. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    12
    47
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0.6 ± 2.2
    -0.3 ± 4.8
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Week 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Week 96
    End point description
    The WASI-II: Vocabulary test is a quick estimate of an individual’s level of intellectual functioning which comprised of 31 total items that require the subject to orally define 3 images and 28 words presented both orally and visually. Items 1 to 3 rated on a score of 0 or 1, items 4 and 5 rated on a score of 0 or 2, items 6 to 31 rated on a scale of 0 to 2. Each item score was summed up to derive the total score which was ranged from 0 (minimum score) to 59 (maximum score), where higher score indicated better level of intellectual functioning/higher level of intelligence. Analysis was performed on ITT population. Here, "Number of subjects analysed" = subjects with available data for this endpoint. 99999 was used as a space filler and specified that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    1
    1
    Units: scores on a scale
        arithmetic mean (standard deviation)
    5.0 ± 99999
    4.0 ± 99999
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Week 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Week 96
    End point description
    Letter fluency is a condition measured in Delis-Kaplan Executive Function System (D-KEFS). Subjects are asked to name as many words as they can, starting with a specified letter for 60 seconds. The words cannot be names, places, numbers or grammatical variants of previous answers. Repeated answers are not scored as a correct response. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials and a letter fluency score is given. A higher score is considered better. There is no set range as the score depends on how many correct words the subject relays in the given time period. Analysis was performed on ITT population. Here, “number of subjects analysed”=subjects with available data for this endpoint. Here, 99999 was used as a space filler and specified that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    1
    2
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -3.0 ± 99999
    4.0 ± 9.9
    No statistical analyses for this end point

    Secondary: Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Week 96

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    End point title
    		 Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Week 96
    End point description
    Category fluency is a condition measured in the D-KEFS. It measures subject's ability to generate words from three different categories (e.g., fruits, vegetables and animals), within a minute for each category. Total score is number of correct words for each category with no points for repetitions or non-words. Score range 0 to unlimited, where 0 = low score, higher score indicates better performance. Analysis was performed on ITT population. Here, “number of subjects Analysed”=subjects with available data for this endpoint. Here, 99999 was used as a space filler and specified that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    1
    2
    Units: score on a scale
        arithmetic mean (standard deviation)
    6.0 ± 99999
    5.0 ± 5.7
    No statistical analyses for this end point

    Secondary: Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Week 96

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    End point title
    		 Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Week 96
    End point description
    SRT is a test to assess verbal learning and memory. During the administration of the SRT only the examiner and the subject should be in the testing room. A list of twelve words is read aloud by the examiner at a rate of one word per two seconds. The subject is asked to recall all twelve words after a 30 minute delay. Only the words that are missed on the preceding trial are given in the consecutive trial. The total score represents a sum score of total 6 trials, therefore the range is from 0-72. The lower the value the worse the outcome, higher value indicates better recall. Analysis was performed on ITT population. Here, “number of subjects analysed”=subjects with available data for this endpoint. 99999 was used as a space filler and specified that the standard deviation was not calculated, since only 1 subject was assessed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Placebo Teriflunomide
    Number of subjects analysed
    1
    2
    Units: scores on a scale
        arithmetic mean (standard deviation)
    1.0 ± 99999
    -0.5 ± 2.1
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide

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    End point title
    		 Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
    End point description
    Ctrough was defined as the concentration reached by the drug before the next dose is administered. Data for this endpoint was planned to be collected and analysed separately for each dose of teriflunomide. Analysis was performed on PK population which included all randomised subjects exposed to double-blind study medication and had at least 1 PK sample taken. PK samples for teriflunomide 3.5 mg were collected during the PK run-in but all subjects were switched to teriflunomide 7 mg after Week 8. Hence, plasma concentration of teriflunomide 7 mg and 14 mg were reported. Here, ‘number of subjects analysed’=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Week 36
    End point values
    		 Teriflunomide 7 mg Teriflunomide 14 mg
    Number of subjects analysed
    10
    66
    Units: micrograms per millilitre
        arithmetic mean (standard deviation)
    53.1 ± 25.3
    67.8 ± 41.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from signature of the informed consent form up to 96 weeks.
    Adverse event reporting additional description
    Reported AEs were treatment-emergent AEs (TEAEs), that developed/worsened during TEAE period (time from 1st intake of investigational medicinal product (IMP) to last intake of IMP in 96-weeks double-blind treatment period). Safety population: all randomized subjects exposed to double-blind study drug, regardless of amount of treatment administered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matching to teriflunomide tablet orally QD for 96 weeks.

    Reporting group title
    Teriflunomide
    Reporting group description
    		 Subjects received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on subjects predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <=95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.

    Serious adverse events
    		 Placebo Teriflunomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 57 (10.53%)
    12 / 109 (11.01%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint Dislocation
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Nerve Injury
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Familial Mediterranean Fever
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiomyopathy
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal Fissure
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Fistula
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Teriflunomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 57 (70.18%)
    85 / 109 (77.98%)
    Vascular disorders
    Orthostatic Hypotension
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 109 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 109 (3.67%)
         occurrences all number
    5
    6
    Influenza Like Illness
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
         occurrences all number
    1
    3
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 109 (3.67%)
         occurrences all number
    0
    4
    Pyrexia
         subjects affected / exposed
    2 / 57 (3.51%)
    6 / 109 (5.50%)
         occurrences all number
    2
    9
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 109 (0.92%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 57 (5.26%)
    6 / 109 (5.50%)
         occurrences all number
    3
    7
    Dyspnoea
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    3
    Nasal Congestion
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
         occurrences all number
    1
    3
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 57 (3.51%)
    7 / 109 (6.42%)
         occurrences all number
    2
    8
    Rhinitis Allergic
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 109 (3.67%)
         occurrences all number
    3
    6
    Depression
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 109 (1.83%)
         occurrences all number
    2
    2
    Insomnia
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 109 (0.00%)
         occurrences all number
    3
    0
    Investigations
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 109 (3.67%)
         occurrences all number
    0
    6
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    5
    Protein Urine Present
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
         occurrences all number
    1
    4
    Weight Decreased
         subjects affected / exposed
    2 / 57 (3.51%)
    6 / 109 (5.50%)
         occurrences all number
    2
    7
    Weight Increased
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    4
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 57 (1.75%)
    4 / 109 (3.67%)
         occurrences all number
    1
    7
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    3 / 57 (5.26%)
    4 / 109 (3.67%)
         occurrences all number
    6
    4
    Contusion
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 109 (3.67%)
         occurrences all number
    0
    4
    Fall
         subjects affected / exposed
    4 / 57 (7.02%)
    6 / 109 (5.50%)
         occurrences all number
    5
    8
    Ligament Sprain
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
         occurrences all number
    2
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 57 (7.02%)
    9 / 109 (8.26%)
         occurrences all number
    5
    9
    Headache
         subjects affected / exposed
    13 / 57 (22.81%)
    18 / 109 (16.51%)
         occurrences all number
    18
    30
    Hypoaesthesia
         subjects affected / exposed
    3 / 57 (5.26%)
    6 / 109 (5.50%)
         occurrences all number
    5
    7
    Paraesthesia
         subjects affected / exposed
    1 / 57 (1.75%)
    12 / 109 (11.01%)
         occurrences all number
    2
    20
    Presyncope
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    3
    Tremor
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
         occurrences all number
    3
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
         occurrences all number
    1
    3
    Neutropenia
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    5
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 109 (2.75%)
         occurrences all number
    2
    3
    Tinnitus
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 109 (2.75%)
         occurrences all number
    1
    3
    Eye disorders
    Eye Pain
         subjects affected / exposed
    4 / 57 (7.02%)
    4 / 109 (3.67%)
         occurrences all number
    8
    4
    Vision Blurred
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 109 (1.83%)
         occurrences all number
    3
    3
    Visual Impairment
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 109 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 57 (1.75%)
    12 / 109 (11.01%)
         occurrences all number
    1
    15
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 57 (3.51%)
    6 / 109 (5.50%)
         occurrences all number
    2
    9
    Diarrhoea
         subjects affected / exposed
    4 / 57 (7.02%)
    8 / 109 (7.34%)
         occurrences all number
    4
    9
    Nausea
         subjects affected / exposed
    4 / 57 (7.02%)
    9 / 109 (8.26%)
         occurrences all number
    5
    11
    Vomiting
         subjects affected / exposed
    5 / 57 (8.77%)
    5 / 109 (4.59%)
         occurrences all number
    5
    6
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 109 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 57 (7.02%)
    5 / 109 (4.59%)
         occurrences all number
    4
    5
    Alopecia
         subjects affected / exposed
    7 / 57 (12.28%)
    23 / 109 (21.10%)
         occurrences all number
    7
    25
    Rash
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
         occurrences all number
    2
    4
    Endocrine disorders
    Autoimmune Thyroiditis
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 57 (5.26%)
    2 / 109 (1.83%)
         occurrences all number
    7
    2
    Back Pain
         subjects affected / exposed
    2 / 57 (3.51%)
    5 / 109 (4.59%)
         occurrences all number
    3
    6
    Muscle Spasms
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 109 (1.83%)
         occurrences all number
    2
    2
    Muscular Weakness
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
         occurrences all number
    2
    1
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    3
    Pain In Extremity
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
         occurrences all number
    2
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 57 (1.75%)
    5 / 109 (4.59%)
         occurrences all number
    1
    5
    Gastroenteritis
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 109 (2.75%)
         occurrences all number
    3
    3
    Influenza
         subjects affected / exposed
    4 / 57 (7.02%)
    10 / 109 (9.17%)
         occurrences all number
    4
    16
    Nasopharyngitis
         subjects affected / exposed
    5 / 57 (8.77%)
    28 / 109 (25.69%)
         occurrences all number
    6
    49
    Pharyngitis
         subjects affected / exposed
    1 / 57 (1.75%)
    7 / 109 (6.42%)
         occurrences all number
    1
    8
    Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 109 (3.67%)
         occurrences all number
    0
    7
    Rhinitis
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
         occurrences all number
    3
    8
    Sinusitis
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
         occurrences all number
    2
    4
    Tinea Versicolour
         subjects affected / exposed
    2 / 57 (3.51%)
    1 / 109 (0.92%)
         occurrences all number
    2
    1
    Tonsillitis
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 109 (3.67%)
         occurrences all number
    2
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 57 (10.53%)
    23 / 109 (21.10%)
         occurrences all number
    23
    64
    Metabolism and nutrition disorders
    Vitamin D Deficiency
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 109 (1.83%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2013
    Following changes were made: 1 MRI added at Weeks 24, 48 and 96 to strengthen MRI data; 1 MRI added at Week 36 in case of at least 5 new/enlarged T2 lesions; change in volume of T2 lesions, change in volume of T1 hypointense lesions, number of new T1 hypointense lesions, and brain atrophy were added and grouped as MRI endpoints; addition of immunoglobulin (IgG, IgM, and IgA) measurements at Baseline and every 24 weeks, aimed to provide additional information on a potential, although not expected, effect of teriflunomide on the immune system in this age group; poisson regression model changed in negative binomial model for the analysis of the number of new or enlarged T2-lesions and the number of T1 Gd-enhancing lesions per MRI scan. Reduced the impact of potential outliers, ordinal logistic regression model including treatment group, region, pubertal status, and age were also used to analyse these endpoints. The Poisson regression model with a robust error variance was to be used in sensitivity analyses.
    26 Jun 2014
    Following changes were made: Extension of the open-label period up to 192 weeks after randomisation; one MRI timepoint added at Week 72; addition of a criterion for switch into open-label period taking this additional MRI scan into account as follows: at least 5 new/enlarged T2 lesions on each of the 2 consecutive MRI scans of Week 48 and Week 72; change in exclusion criteria: the required minimum washout period duration for previous multiple sclerosis (MS) treatment was modified; addition of exclusion criteria: previous treatment with alemtuzumab; addition of a note about the content of teriflunomide tablets (lactose) and that therefore, investigators were to consider whether history of lactose intolerance could affect treatment tolerability; addition of a note about contraception and the association of local additional requirements (United Kingdom) to be followed, e.g., spermicidal foam/gel/film/cream/suppository, as per medicines and healthcare products regulatory agency rules; addition of endpoints: proportion of subjects free of new or enlarged MRI T2-lesions at Weeks 48 and 96. It was specified that the main MRI endpoints were the number of new/newly enlarged T2 lesions and the number of T1 Gd-enhancing T1 lesions; proportion of disease-free subjects as an exploratory endpoint; addition of text to introduce the rationale for placebo-controlled design; addition of endocrine function evaluation consisting of measurement of thyroid stimulating hormone (TSH) every 24 weeks and at end of treatment (EOT); addition of text to specify that local anesthetic was to be offered for blood draws to minimise pain and discomfort; correction of text: Pre-defined adverse events and laboratory abnormalities for specific reporting to restore the instructions that were included in the initial protocol but had been inadvertently taken out in Amended protocol 1.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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